In humans, BAP1 is encoded by the BAP1 gene located on the short arm of chromosome 3.
Structure
Human BAP1 is 729 amino acids long and has three domains:
a ubiquitin carboxyl-terminal hydrolase N-terminuscatalytic domain, which removes ubiquitin from ubiquitylated substrates: residues 1-240, with an active site comprising the Cysteine91, Alanine95, and Glycine178 residues.
a C-terminal domain: residues 598-729, which includes a UCH37-like domain at residues 675-693 and two Nuclear localization sequences at residues 656-661 and 717-722.
Function
In both Drosophila and humans, BAP1 functions as the catalytic subunit of the Polycomb repressive deubiquitinase complex, which controls homeobox genes by regulating the amount of ubiquitinated Histone H2A in Nucleosomes bound to their promoters. In flies and humans, the PR-DUB complex is formed through the interaction of BAP1 and ASXL1 BAP1 has also been shown to associate with other factors involved in chromatin modulation and transcriptional regulation, such as Host cell factor C1, which acts as an adaptor to couple E2Ftranscription factors to chromatin-modifying complexes during cell cycle progression.
In 2010, J. William Harbour and colleagues published a landmark article in Science, in which they used exome sequencing of patient tumor samples and identified inactivating mutations in BAP1 in 47% of uveal melanomas. They were also the first to show germline BAP1 mutations, and that BAP1 mutation was strongly associated with metastasis. These mutations included multiple nonsense mutations and splice site mutations throughout the gene. missense mutations were only found within the UCH and ULD domains, further supporting the requirement for BAP1 catalytic function. This study also identified a germline mutation in one of the uveal melanoma patients, suggesting that, besides being a metastasis suppressor, BAP1 could predispose certain people to more aggressive uveal melanoma tumors.
BAP1 mutations have been identified in aggressive mesotheliomas with similar mutations as seen in melanomas,.
Two studies used genome sequencing independently to identify germline mutations in BAP1 in families with genetic predispositions to mesothelioma and melanocytic skin tumors The atypical melanocytic lesions resemble Spitz nevi and have been characterized as "atypical Spitz tumors", although they have a unique histology and exhibit both BRAF and BAP1 mutations. Further studies have identified germline BAP1 mutations associated with other cancers. These studies suggest that germline mutation of BAP1 results in a linking BAP1 to many more cancers.
Immunochemistry
for BAP1 is a prognostic biomarker to predict poor oncologic outcomes and adverse clinicopathological features in patients with non-metastatic clear cell renal cell carcinoma. BAP1 assessment using immunohistochemistry on needle biopsy may benefit preoperative risk stratification and guide treatment planning.
s have been used in the study of BAP1 function. A conditional knockout mouse line called Bap1tm1aHmgu was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping - in-depth bone and cartilage phenotyping
